TGF? engages MEK/ERK to differentially regulate benign and malignant pancreas cell function.

ABSTRACT: While TGF? signals are anti-proliferative in benign and well-differentiated pancreatic cells, TGF? appears to promote the progression of advanced cancers. To better understand dysregulation of the TGF? pathway, we first generated mouse models of neoplastic disease with TGF? receptor deficiencies. These models displayed reduced levels of pERK irrespective of KRAS mutation. Furthermore, exogenous TGF? led to rapid and sustained TGFBR1-dependent ERK phosphorylation in benign pancreatic duct cells. Similar to results that our group has published in colon cancer cells, inhibition of ERK phosphorylation in duct cells mitigated TGF?-induced upregulation of growth suppressive pSMAD2 and p21, prevented downregulation of the pro-growth signal CDK2 and ablated TGF?-induced EMT. These observations suggest that ERK is a key factor in growth suppressive TGF? signals, yet may also contribute to detrimental TGF? signaling such as EMT. In neoplastic PanIN cells, pERK was not necessary for either TGF?-induced pSMAD2 phosphorylation or CDK2 repression, but was required for upregulation of p21 and EMT indicating a partial divergence between TGF? and MEK/ERK in early carcinogenesis. In cancer cells, pERK had no effect on TGF?-induced upregulation of pSMAD2 and p21, suggesting the two pathways have completely diverged with respect to the cell cycle. Furthermore, inhibition of pERK both reduced levels of CDK2 and prevented EMT independent of exogenous TGF?, consistent with most observations identifying pERK as a tumor promoter. Combined, these data suggest that during carcinogenesis pERK initially facilitates and later antagonizes TGF?-mediated cell cycle arrest, yet remains critical for the pathological, EMT-inducing arm of TGF? signaling.

SUBMITTER: Principe DR 

PROVIDER: S-EPMC5537609 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature